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A randomised, double-blind, controlled trial of the immunogenicity and tolerability of a meningococcal group C conjugate vaccine in young British infants
Vaccine 19 (2001) 1232 – 1238 www.elsevier.com/locate/vaccine
A randomised, double-blind, controlled trial of the immunogenicity and tolerability of a meningococcal group C conjugate vaccine in young British infants M. English a,*, J.M. MacLennan a, J.M. Bowen-Morris a, J. Deeks b, M. Boardman a, K. Brown a, S. Smith a, J. Buttery a,c, J. Clarke d, S. Quataert e, S. Lockhart d, E.R. Moxon a,c b
a Oxford Vaccine Group, Uni6ersity of Oxford, John Radcliffe Hospital, Headington, Oxford, UK ICRF/NHS Centre for Statistics in Medicine, Institute of Health Sciences, Uni6ersity of Oxford, Oxford, UK c Department of Paediatrics, Uni6ersity of Oxford, John Radcliffe Hospital, Headington, Oxford, UK d Wyeth-Lederle Vaccines, Uni6ersity of Oxford, John Radcliffe Hospital, Headington, Oxford, UK e Wyeth-Lederle Vaccines and Pediatrics, 211 Bailey Road, West Henrietta, NY 14586, USA
Received 26 January 2000; received in revised form 26 June 2000; accepted 18 July 2000
Abstract A double-blind, randomised, controlled trial was conducted in 248 British infants to assess the immunogenicity and tolerability of three doses of a meningococcal group C/CRM 197 conjugate vaccine (Lederle Laboratories, USA) given at 2, 3 and 4 months. Control children received three doses of Hepatitis B vaccine (Engerix B®; SmithKline Beecham). At 5 months of age, 100% of children receiving the conjugate vaccine had specific immunoglobulin G concentrations \2.0 mg/ml (n=116) compared with only 4% of control children (n =121). Those receiving the conjugate also had 2.5- and 1.6-fold higher geometric mean concentrations of PRP and diphtheria antibodies, respectively. The vaccine was well tolerated. © 2000 Elsevier Science Ltd. All rights reserved. Keywords: Immunogenicity; Tolerability; Meningococcal group C vaccine; British infants
1. Introduction The introduction of a vaccination programme in the UK to prevent disease due to Haemophilus influenzae type B (Hib) has been extremely successful [1]. Its success is based on the ability of the polysaccharide – protein conjugate vaccine to induce effective short- [2] and long-term (memory) [3] immune responses in young infants. This success has fuelled the development of further conjugate vaccines against other leading bacterial infections. Meningococcal group C infections currently account for approximately 35% of cases of meningococcal disease in England and Wales, and disease incidence appears to be rising [4]. Trials of conju* Corresponding author. Present address: Wellcome Trust Research Laboratories, P.O. Box 230, Kilifi, Kenya. Fax: +254-12522390. E-mail address: [email protected] (M. English).
gate vaccines against this pathogen demonstrate both immunogenicity in young infants and the induction of immunologic memory [5–8]. Such studies underlie the recent introduction of a programme of meningococcal group C vaccination [9] in the United Kingdom prior to an absolute demonstration of efficacy. However, the expansion of routine immunisation programmes increases the potential for unforeseen interactions particularly as many potential new vaccines share components. In previous studies in UK infants of either Group A + C [5] or Group C only [7] meningococcal/CRM197 conjugate vaccines, there have either been no control group [5] or a Hib–tetanus conjugate vaccine has been used [7] making conjugate-related interactions impossible to examine. We now report the findings of a randomised, double-blind, controlled trial of a meningococcal group C conjugate vaccine among a group of children receiving a Hib vaccine conjugated to the same carrier. Both vaccines are licensed for use in
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M. English et al. / Vaccine 19 (2001) 1232–1238
the UK national immunisation programme. This study increases the body of data on the immunogenicity and tolerability of the new meningococcal vaccine, and allows the potential for interaction with structurally related vaccines to be examined.
2. Methods
2.1. Patient population Newborn infants registered with pre-selected, consenting general practices (comprising 31 of the 88 Oxfordshire practices) were identified from birth records at two Oxfordshire hospitals between April and November 1997. Parents of these infants were invited by letter to consider their child for inclusion in the study. Those who expressed an initial interest received further information by post, telephone and, occasionally, home visit. Infants were excluded from the study if: the birthweight was less than 2 kg; routine immunisations (other than BCG) had already been given; the first vaccination could not be given between 7 and 10 weeks of age; the family had plans to move out of the study area or would not be able to comply with the vaccination schedule over the complete study period; an infant had contracted one of the vaccine preventable diseases (including meningococcal disease) prior to enrolment; there was a documented history of cerebral damage in the neonatal period; a contra-indication to routine immunisation was detected at or prior to the routine 8-week check; or the parent declined one of the routine immunisations.
2.2. Vaccines Diphtheria, tetanus and pertussis (Trivax®, Batch no. E7112C; Evans/Wellcome), Hib (HibTITER®, Batch no. L0342B1; Wyeth), Hepatitis B (Engerix B®, Batch nos. Eng 2069B2 and 1687A2; SmithKline Beecham) and oral polio vaccines (OPV) were obtained from commercial stock. The meningococcal conjugate vaccine was supplied as single-dose vials by Lederle Laboratories (USA). Each dose contains approximately 10 mg group C meningococcal oligosaccharide, 25 mg CRM197 protein and 0.5 mg aluminium phosphate as adjuvant. CRM197 is a variant diphtheria toxoid and is the same carrier protein as used in HibTITER®.
2.3. Study procedure The central pharmacy made up study vaccines for each subject according to a single computer-generated randomisation schedule with block size 4, infants being allocated to receive the Meningitis C conjugate vaccine or a Hepatitis B vaccine as a control. Study vaccines
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were given either at home or in specific study clinics with infants allocated sequential subject numbers depending only on the anticipated date of vaccination. Once consent was obtained and if, at this first vaccination visit, consent was not obtained or the child was assessed to be unfit according to national guidelines [1] the study number was re-allocated to the next enrolled child. All study personnel and parents were blind to the vaccine allocation. Vaccines were pre-prepared by the central pharmacy in identical syringes with circumferential opaque labels containing equal volumes of fluid of the same colour and consistency. A maximum of 6 h storage in a temperature-controlled coolbox was allowed to elapse after vaccine re-constitution before the vaccine was administered. Routine vaccines were given into the left thigh, the study vaccine into the right thigh, and OPV was given orally. The code for vaccine allocation was only broken at the end of the study. Members of the study team were trained to recognise and manage acute, severe adverse events and a member of the study team was present for a minimum of 15 min after each vaccine was given. Parents were asked to complete a standard diary card (available on request) after each vaccination episode. This record included twice-daily axillary temperature measurements and an assessment of any local or systemic reactions for the 3 days after immunisation. Parents were telephoned during this 3-day observation period to ask about adverse reactions and a team member was available on a 24-h basis to answer any queries throughout the study. For local reactions, a simple calliper device was supplied for measurement of the extent of redness and swelling at injection sites. Tenderness at the injection site was considered significant if the child cried when the site was touched and/or if the limb was moved. For the purposes of analysis, the maximum recorded systemic or local reaction over the 3-day observation period was used to describe each vaccination episode. Severe local and systemic adverse reactions were classified in accordance with UK national guidelines [1] and affected infants were immediately withdrawn from the trial. Illnesses among study children and treatments sought during the study were also documented at each visit, and a decision by the study paediatricians was made about the likely relationship of these illnesses to the receipt of vaccine (graded as not related, remote, possible, probable, definite). Venepuncture was performed before administration of the first vaccines at the 2month visit and at approximately 5 months of age, 1 month after administration of the third round of vaccines.
2.4. Antibody assays Individual antibody concentrations to the following antigens were measured by standard enzyme-linked im-
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munosorbent assay (ELISA) techniques (immunoglobulin (Ig)G unless stated otherwise): diphtheria toxoid, tetanus toxoid, pertussis toxoid, fimbriae and FHA, H. influenzae polyribosyl phosphate (PRP-Ig). Specific IgG levels for group C meningococci were measured by ELISA (Wyeth Laboratories, Rochester, USA) and for a random sample of children at 5 months of age titres were also measured using a functional bactericidal assay (Wyeth-Lederle Laboratories, UK). A minimum antibody level of ] 0.01 IU/ml is considered protective against tetanus and diphtheria with ideal levels ] 0.1 IU/ml. For protection against H. influenzae type b disease, a lower limit for anti-PRP antibodies of ] 0.15 mg/ml is required, while recommended post-vaccination levels are ] 1.0 mg/ml. Although a protective antibody level against group C meningococci has yet to be demonstrated formally, a level above 2 mg/ml is considered likely to be protective [10]. On a randomly selected subgroup of the 5-month sera, the bactericidal activity was also quantified. The assay used measures the average final dilution of serum resulting in ]50% killing of Neisseria meningitidis C strain C11 in the presence of freshly thawed baby rabbit complement compared with similarly treated control organisms lacking patient serum [11].
2.5. Ethical appro6al Prior to the start of the study, ethical approval was received from the Central Oxford Research Ethics Committee. Specific approval was sought from the general practitioners in the pre-defined study areas before eligible infants were approached, and written informed consent from a parent was required before an infant entered the study.
2.6. Sample size, data handling and statistical analysis The primary aim of the study was to determine the response to meningococcal C conjugate vaccine. A sample size of 120 infants in each group was chosen to be able to detect a 1.5-fold difference in the geometric mean titre (GMT) of specific IgG against group C meningococci between active and comparator groups with 80% power at P =0.05, assuming a (natural log) standard deviation of 1.0 (based on previous data). This sample size would also allow approximately 1.6and 1.9-fold differences in the GMTs of antibodies against diphtheria and PRP (Hib) between the groups (testing for interaction) to be detected with similar power All data were recorded in individual case reference forms identified by a study number. Data were then double entered, and range and consistency checked and verified by an independent data management company (SGS Biopharma, Belgium) prior to analysis. Compari-
son of dichotomous outcomes was made using Fisher’s exact test. Absolute antibody levels and titres were log-transformed prior to analysis, the geometric means (presented with 95% confidence intervals) in each study group being compared using the t-test. Within-patient comparisons of local reactions to study and routine vaccines were carried out using McNemar’s test for matched pairs. The principal analysis was performed on an intention-to-treat basis, and all analyses were performed by investigators in Oxford using the software programme STATA 6.0 (Stata Corporation, USA).
3. Results The allocation of infants and their course within the trial is given in Fig. 1. Five of the randomised infants were withdrawn from the study, three at the parents request (two hepatitis B group, one meningococcal group) and two with severe systemic adverse reactions (one hepatitis B group with inconsolable crying, one meningococcal group with fever of 40°C). There were no severe local reactions. There were no other adverse reactions thought to be probably or definitely related to vaccination. Three adverse events were considered possibly related but these did not result in withdrawal of infants from the study. They was mild eczema after third vaccinations (meningococcal group), persistent crying after third vaccinations (hepatitis B group) and irritability with mild fever after third vaccinations (hepatitis B group). One further child received the wrong vaccine at the third visit and no specimen was taken for analysis at 5 months. In addition, no blood was available for analysis at 5 months from five children in the meningococcal group (venesection attempts failed, n= 3; broken specimen tube, n= 1; sample not taken because delay from second to third dose of vaccines was 58 days, n=1). As a result, data from 237 infants (116 meningococcal group and 121 hepatitis B group) were available for an intention to treat analysis of immunogenicity. All vaccination episodes including those up until the time of withdrawal in those leaving the study were included in the assessment of adverse events and tolerability (total=732). Seven children would have been excluded from a strict per-protocol analysis of immunogenicity, four in the meningococcal group and three in the control group. Reasons for per-protocol exclusions included: study vaccine given after maximum permissable time from preparation (one vaccine episode in each of two patients in the meningococcal group); number of days between vaccinations B 28 days or \42 days (five episodes in three hepatitis B group patients and two meningococcal group patients). The exclusion of these
M. English et al. / Vaccine 19 (2001) 1232–1238
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Fig. 1. Trial profile.
latter patients and performance of a strict per-protocol analysis did not significantly alter any of the study findings (data available on request) and thus only the intention-to-treat analysis is presented. In addition, although it could be shown that the magnitude of the 2-month concentration was a statistically significant determinant of the 5-month concentration, only unadjusted comparisons are reported. Including 2-month concentrations as a co-variate in the analyses made no clinical difference to the magnitude of the results and no difference to the significance of statistical comparisons. The basic demographic details and baseline antibody concentrations of those included in the intention to treat analysis are given in Table 1. There were no significant differences between the meningococcal and hepatitis B control groups. The results of antibody assays at 5 months are presented in Table 2. Meningococcal group C antibody titres were 248 (95% CI, 194 317) times higher in the intervention group than in the control group. Antibodies to PRP and Diphtheria were likewise, respectively, 2.5 (95% CI, 1.7, 3.7) and 1.6 (95% CI, 1.3, 2.0) times higher in the intervention compared with the control group. There were no significant differences in the ratios of the geometric mean concentrations for the other antibodies. Serum bactericidal assays were performed on specimens collected at 5 months on 117 children, 58 of whom received meningococcal vaccine. Geometric mean titres were 2.9 (95% CI, 1.8, 4.9) in the control group and 1428.7 in the meningococcal group (95% CI, 1125.1, 1814.3). The pattern of responses determined by ELISA and SBA titre in the intervention and control groups, and the
relationship between the SBA titres and the ELISA concentrations are depicted in Fig. 2. All 58 children receiving the meningococcal vaccine with samples analysed achieved both an ELISA-measured specific Table 1 Demographic and baseline serological data Meningococcal C group (n =116) [95% CI] Percentage male 56% [47%, 65%] Age at first 61.1 [60.4, 61.9] blood/vaccination (days) Age at second blood 153.7 [152.1, 155.3] (days) Geometric mean 0.17 [0.14, 0.21] PRP titre (mg/ml) Geometric mean 0.13 [0.10, 0.17] meningococcal C titre (mg/ml) Geometric mean 0.50 [0.41, 0.61] tetanus titre (IU/ml) Geometric mean 0.01 [0.01, 0.01] Diphtheria titre (IU/ml) Geometric mean 2.93 [2.38, 3.60] pertussis toxoid (U/ml) Geometric mean 9.15 [7.61, 11.0] pertussis FHA (U/ml) Geometric mean 0.79 [0.66, 0.95] pertussis fimbriae (U/ml)
Hepatitis B group (n =121) [95% CI]
55% [45%, 63%] 60.2 [59.4, 61.0]
152.6 [151.2, 154.1] 0.15 [0.12, 0.19] 0.17 [0.12, 0.22]
0.55 [0.44, 0.68]
0.01 [0.01, 0.01]
3.28 [2.66, 4.04]
8.34 [6.93, 10.0]
0.91 [0.75, 1.10]
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Table 2 Serological response at 5 months to vaccination schedule (ITT analysis)a Meningococcal C group (n =116) [95% CI] Response to study vaccines Response to Hib vaccine Response to diphtheria toxoid Response to tetanus toxoid Response to pertussis vaccine.
Geometric mean meningococcal C 23.93 [21.47, 24.68] concentration (mg/ml) Proportion ]2.0 (mg/ml) 100% [96%, 100%] Geometric mean PRP concentration (mg/ml) 9.83 [7.72, 12.50] Proportion ]1.0 (mg/ml) 94% [88%, 97%] Proportion ]0.15 (mg/ml) 100% [96%, 100%] Geometric mean (IU/ml) Diphtheria 1.77 [1.54, 2.04] concentration Proportion ]0.1 (IU/ml) 100% [96%, 100%] Geometric mean tetanus concentration (IU/ml) 5.81 [5.06, 6.68]
Hepatitis B group (n = 121) [95% CI]
P value for difference
0.10 [0.08, 0.12]
B0.001
4% [2%, 10%] 3.90b [2.91, 5.22] 78% [69%, 84%] 99% [95%, 100%] 1.07b [0.93, 1.25]
B0.001 B0.001 B0.001 1.0 B0.001
100% [96%, 100%] 6.39 [5.52, 7.39]
– 0.4
Geometric mean pertussis toxoid concentration (U/ml)
4.23 [3.48, 5.14]
4.47 [3.66, 5.47]
0.7
Geometric mean pertussis FHA concentration (U/ml) Geometric mean pertussis fimbriae concentration (U/ml)
15.38 [13.46, 17.57]
15.43 [13.24, 17.98]
1.0
25.01 [21.24, 29.25]
26.59 [22.22, 31.82]
0.6
a There were no differences in the proportions of children achieving tetanus titres ]0.01 or 0.1 between groups and no differences in proportions achieving a twofold or greater rise in pertussis responses between groups. b n= 120.
IgG \ 2 mg/ml and an SBA titre \1 in 8 at 5 months, both thought to be clinically significant responses. Among the 59 control children tested, eight demonstrated a SBA titre\ 1 in 8 without achieving a specific IgG response \ 2 mg/ml, and three had a specific IgG response \2 mg/ml but a low or absent response in the SBA assay. Data from more than 93% of vaccination episodes were available for examining the prevalence of mild systemic adverse reactions that were commonly reported (illustrated with data from the 4-month vaccinations in Table 3). Temperatures were available for analysis in 89% of cases and, in these, fever was uncommon (B 3% episodes overall were associated with a temperature \37.9°C). No statistically significant differences in reporting were observed between treated and control groups at 2, 3 or 4 months. Comparison of local reactions to the hepatitis B vaccine and meningococcal group C vaccine also failed to demonstrate any difference at any stage (illustrative data at 4 months is given in Table 3). However, local reactions to the study vaccines were also compared with the simultaneously administered routine DTP/Hib vaccines given in a different leg. Routine vaccines were associated with redness and swelling (of any degree) more often than either study vaccine at each dose (P 5 0.01 for each comparison), although such an obvious difference was not apparent for tenderness (illustrative data at 4 months is given in Table 3).
4. Discussion Three doses of a vaccine comprising the meningococcal group C oligosaccharide conjugated to CRM197 (a variant diphtheria toxoid) with an alum adjuvant produced a marked, specific IgG response when administered to 116 children at 2, 3 and 4 months of age. The geometric mean meningococcal group C antibody titre (23.9 mg/ml) was comparable with results in previous
Fig. 2. Scatter plot of log2 values of meningococcal group C serum bactericidal titre (y axis) and log10 antibody concentration (mg/ml) measured by ELISA (x axis) from individuals aged 5 months. Grey circles, Meningococcal group C conjugate vaccine recipients (n= 59); black squares, ELISA concentrations \2 mg/ml are found to the right of the dashed, vertical line, and SBA titres \1 in 8 are found above the solid horizontal line.
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Table 3 Proportion of children vaccinated at 4 months (third vaccination) with associated systemic and local adverse reactions during the 3-day observation period
Crying more than expected Fever ]38°C Irritability Sleeping through a feed Any redness at study vaccine site Any swelling at study vaccine site Any tenderness at study vaccine site Any redness at routine vaccine site Any swelling at routine vaccine site Any tenderness at routine vaccine site
Meningococcal C Group (maximum n=122)
Hepatitis B group (maximum n = 121)
P value for difference
15/115 5/101 81/121 24/114 46/113 7/112 15/113 66/115 28/113 20/111
9/109 (8%) 1/98 (1%) 75/112 (67%) 14/109 (13%) 45/113 (40%) 9/111 (8%) 16/110 (15%) 63/112 (56%)b 20/110 (18%)b 21/110 (19%)b
0.3 0.2 1.0 0.11 1.0 0.6 0.8
(13%) (5%) (67%) (21%) (41%) (6%) (13%) (57%)a (25%)a (18%)a
a Number of matched pairs for analysis is 112, 110 and 111 for redness, swelling and tenderness, respectively; PB0.01 for comparison of proportions for those experiencing any redness or swelling at meningococcal vaccine site and routine vaccine site. b Number of matched pairs for analysis is 111, 109 and 109 for redness, swelling and tenderness, respectively; PB0.01 for comparison of proportions for those experiencing any redness or swelling at Hepatitis B vaccine site and routine vaccine site.
studies using similar vaccines (GMT=38.59 mg/ml [12] and 13.1 mg/ml [6]) although non-IgG-specific ELISAs were used in the these studies. In one of these previously reported studies [12], all 56 children receiving a meningococcal group C conjugate vaccine at the UK schedule achieved an antibody concentration \ 2 mg/ml at 5 months, as occurred in our study. In both cases, this was associated with serum bactericidal activity ] 1 in 8 (a titre thought likely to protect individuals from disease [10]) in all children. Another recent UK study using a different meningococcal group C conjugate vaccine reported similar results in 62 children in whom serum bactericidal titres were measured [7]. These studies therefore provide important evidence that a functional immune response results from this class of vaccine. Interestingly, however, despite the obvious concordance of results from the ELISA assays and serum bactericidal assays in children receiving the meningococcal conjugate vaccine among control children, high concentrations of specific IgG antibody and high titre serum bactericidal activity, when present, were often discrepant (Fig. 2). One explanation might be the presence of naturally acquired non-IgG immunoglobulin classes in the functional assay that would not be detected using the IgG-specific ELISA technique. As important to a national immunisation programme as the immunogenicity data presented in this paper are recent data indicating that meningococcal group C conjugate vaccines are also likely to induce effective immunologic memory, and thus long-lasting immunity [6,7] after administration at 2, 3 and 4 months. In practice, acceptance of this vaccine may also be aided as it appears to be well tolerated with few systemic reactions or significant local reactions occurring. How-
ever, although meningococcal group C disease is a major public health issue, it is still a relatively rare disease. Proving the effectiveness and safety of this vaccine will therefore either depend on the conduct of extremely large intervention trials ( 500 000 infants [12]) or reliable disease surveillance as part of the intervention program. Paradoxically, demonstrating effectiveness may become easier if the currently high incidence of meningococcal disease [4] is sustained and reliable information on the serogroup of invasive isolates continues to be available. While the overwhelming majority of cases of meningococcal disease in the United Kingdom are attributed to group B or group C organisms, this is not always the case world-wide. Group A organisms are responsible for major epidemics, particularly in the sub-Sahelian states of Africa [13], while group Y and group W135 organisms may cause a significant number of cases in some countries [14,15]. Clearly, a group C specific vaccine will not protect against these other pathogens. Three factors may therefore limit the apparent degree of protection afforded by this vaccine: travel to areas where non-group C organisms are common [16]; a change in the epidemiology of invasive disease (particularly the emergence of group A, Y or W135 disease) [15]; or the possibility that the vaccine will induce an adaptive switch to other capsular groups or non-encapsulated forms [15,17,18]. Multivalent meningococcal vaccines may provide a partial answer to some of these problems. However, multivalent pneumococcal conjugate vaccines (seven to nine serotypes) are also being assessed in Phase III trials [19], and these pneumococcal vaccines may be available to national immunisation programmes shortly. The possible effects on current routine vaccina-
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tions therefore require consideration. In this study, a positive interaction was demonstrated between vaccines with some structural similarities (diphtheria toxoid, and the Hib and meningococcal conjugate vaccines that use a variant diphtheria toxoid as a carrier). One possible mechanism for this is the generation of a large cross-reactive T helper cell population. While this may be beneficial, some work has already suggested that, as the dose of a specific carrier protein administered increases, there may be a deleterious effect on response to vaccines. Thus, using a four-valent pneumococcal – tetanus toxoid conjugate in infants also receiving a Hib– tetanus toxoid conjugate and tetanus toxoid alone, Dagan et al. demonstrated a fall in response to the Hib and tetanus vaccines as the total dose of carrier (tetanus toxoid) increased [20]. As the effect on seroconversion rates was marginal, the significance of this finding is hard to gauge, but clearly such a possibility needs to be considered as an increasing number of vaccines become available. Furthermore, if public confidence is to be maintained, clear evidence will be required of the potential benefits and safety of an ever-expanding vaccination strategy.
[4] [5]
[6]
[7]
[8]
[9]
[10] [11]
Acknowledgements The contributions made by the authors were as follows: Mike English, involved in design, data collection, analysis and preparation of the manuscript; Jenny MacLennan, contributed to design, data collection and preparation of the manuscript; Jane Bowen-Morris, contributed to design, data collection and preparation of the manuscript; Jon Deeks, contributed to design, analysis and preparation of the manuscript; Maggie Boardman, Jim Buttery, Karen Brown and Sandra Smith, contributed to data collection and preparation of the manuscript; S. Quataert, responsible for development of the specific laboratory assays and the performance of these assays; and Jane Clarke, Steven Lockhart and Prof. E.R. Moxon, responsible for initiating the study, contributed to design and preparation of the manuscript.
[12]
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A randomised, double-blind, controlled trial of the immunogenicity and tolerability of a meningococcal group C conjugate vaccine in young British infants M. English a,*, J.M. MacLennan a, J.M. Bowen-Morris a, J. Deeks b, M. Boardman a, K. Brown a, S. Smith a, J. Buttery a,c, J. Clarke d, S. Quataert e, S. Lockhart d, E.R. Moxon a,c b
a Oxford Vaccine Group, Uni6ersity of Oxford, John Radcliffe Hospital, Headington, Oxford, UK ICRF/NHS Centre for Statistics in Medicine, Institute of Health Sciences, Uni6ersity of Oxford, Oxford, UK c Department of Paediatrics, Uni6ersity of Oxford, John Radcliffe Hospital, Headington, Oxford, UK d Wyeth-Lederle Vaccines, Uni6ersity of Oxford, John Radcliffe Hospital, Headington, Oxford, UK e Wyeth-Lederle Vaccines and Pediatrics, 211 Bailey Road, West Henrietta, NY 14586, USA
Received 26 January 2000; received in revised form 26 June 2000; accepted 18 July 2000
Abstract A double-blind, randomised, controlled trial was conducted in 248 British infants to assess the immunogenicity and tolerability of three doses of a meningococcal group C/CRM 197 conjugate vaccine (Lederle Laboratories, USA) given at 2, 3 and 4 months. Control children received three doses of Hepatitis B vaccine (Engerix B®; SmithKline Beecham). At 5 months of age, 100% of children receiving the conjugate vaccine had specific immunoglobulin G concentrations \2.0 mg/ml (n=116) compared with only 4% of control children (n =121). Those receiving the conjugate also had 2.5- and 1.6-fold higher geometric mean concentrations of PRP and diphtheria antibodies, respectively. The vaccine was well tolerated. © 2000 Elsevier Science Ltd. All rights reserved. Keywords: Immunogenicity; Tolerability; Meningococcal group C vaccine; British infants
1. Introduction The introduction of a vaccination programme in the UK to prevent disease due to Haemophilus influenzae type B (Hib) has been extremely successful [1]. Its success is based on the ability of the polysaccharide – protein conjugate vaccine to induce effective short- [2] and long-term (memory) [3] immune responses in young infants. This success has fuelled the development of further conjugate vaccines against other leading bacterial infections. Meningococcal group C infections currently account for approximately 35% of cases of meningococcal disease in England and Wales, and disease incidence appears to be rising [4]. Trials of conju* Corresponding author. Present address: Wellcome Trust Research Laboratories, P.O. Box 230, Kilifi, Kenya. Fax: +254-12522390. E-mail address: [email protected] (M. English).
gate vaccines against this pathogen demonstrate both immunogenicity in young infants and the induction of immunologic memory [5–8]. Such studies underlie the recent introduction of a programme of meningococcal group C vaccination [9] in the United Kingdom prior to an absolute demonstration of efficacy. However, the expansion of routine immunisation programmes increases the potential for unforeseen interactions particularly as many potential new vaccines share components. In previous studies in UK infants of either Group A + C [5] or Group C only [7] meningococcal/CRM197 conjugate vaccines, there have either been no control group [5] or a Hib–tetanus conjugate vaccine has been used [7] making conjugate-related interactions impossible to examine. We now report the findings of a randomised, double-blind, controlled trial of a meningococcal group C conjugate vaccine among a group of children receiving a Hib vaccine conjugated to the same carrier. Both vaccines are licensed for use in
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the UK national immunisation programme. This study increases the body of data on the immunogenicity and tolerability of the new meningococcal vaccine, and allows the potential for interaction with structurally related vaccines to be examined.
2. Methods
2.1. Patient population Newborn infants registered with pre-selected, consenting general practices (comprising 31 of the 88 Oxfordshire practices) were identified from birth records at two Oxfordshire hospitals between April and November 1997. Parents of these infants were invited by letter to consider their child for inclusion in the study. Those who expressed an initial interest received further information by post, telephone and, occasionally, home visit. Infants were excluded from the study if: the birthweight was less than 2 kg; routine immunisations (other than BCG) had already been given; the first vaccination could not be given between 7 and 10 weeks of age; the family had plans to move out of the study area or would not be able to comply with the vaccination schedule over the complete study period; an infant had contracted one of the vaccine preventable diseases (including meningococcal disease) prior to enrolment; there was a documented history of cerebral damage in the neonatal period; a contra-indication to routine immunisation was detected at or prior to the routine 8-week check; or the parent declined one of the routine immunisations.
2.2. Vaccines Diphtheria, tetanus and pertussis (Trivax®, Batch no. E7112C; Evans/Wellcome), Hib (HibTITER®, Batch no. L0342B1; Wyeth), Hepatitis B (Engerix B®, Batch nos. Eng 2069B2 and 1687A2; SmithKline Beecham) and oral polio vaccines (OPV) were obtained from commercial stock. The meningococcal conjugate vaccine was supplied as single-dose vials by Lederle Laboratories (USA). Each dose contains approximately 10 mg group C meningococcal oligosaccharide, 25 mg CRM197 protein and 0.5 mg aluminium phosphate as adjuvant. CRM197 is a variant diphtheria toxoid and is the same carrier protein as used in HibTITER®.
2.3. Study procedure The central pharmacy made up study vaccines for each subject according to a single computer-generated randomisation schedule with block size 4, infants being allocated to receive the Meningitis C conjugate vaccine or a Hepatitis B vaccine as a control. Study vaccines
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were given either at home or in specific study clinics with infants allocated sequential subject numbers depending only on the anticipated date of vaccination. Once consent was obtained and if, at this first vaccination visit, consent was not obtained or the child was assessed to be unfit according to national guidelines [1] the study number was re-allocated to the next enrolled child. All study personnel and parents were blind to the vaccine allocation. Vaccines were pre-prepared by the central pharmacy in identical syringes with circumferential opaque labels containing equal volumes of fluid of the same colour and consistency. A maximum of 6 h storage in a temperature-controlled coolbox was allowed to elapse after vaccine re-constitution before the vaccine was administered. Routine vaccines were given into the left thigh, the study vaccine into the right thigh, and OPV was given orally. The code for vaccine allocation was only broken at the end of the study. Members of the study team were trained to recognise and manage acute, severe adverse events and a member of the study team was present for a minimum of 15 min after each vaccine was given. Parents were asked to complete a standard diary card (available on request) after each vaccination episode. This record included twice-daily axillary temperature measurements and an assessment of any local or systemic reactions for the 3 days after immunisation. Parents were telephoned during this 3-day observation period to ask about adverse reactions and a team member was available on a 24-h basis to answer any queries throughout the study. For local reactions, a simple calliper device was supplied for measurement of the extent of redness and swelling at injection sites. Tenderness at the injection site was considered significant if the child cried when the site was touched and/or if the limb was moved. For the purposes of analysis, the maximum recorded systemic or local reaction over the 3-day observation period was used to describe each vaccination episode. Severe local and systemic adverse reactions were classified in accordance with UK national guidelines [1] and affected infants were immediately withdrawn from the trial. Illnesses among study children and treatments sought during the study were also documented at each visit, and a decision by the study paediatricians was made about the likely relationship of these illnesses to the receipt of vaccine (graded as not related, remote, possible, probable, definite). Venepuncture was performed before administration of the first vaccines at the 2month visit and at approximately 5 months of age, 1 month after administration of the third round of vaccines.
2.4. Antibody assays Individual antibody concentrations to the following antigens were measured by standard enzyme-linked im-
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munosorbent assay (ELISA) techniques (immunoglobulin (Ig)G unless stated otherwise): diphtheria toxoid, tetanus toxoid, pertussis toxoid, fimbriae and FHA, H. influenzae polyribosyl phosphate (PRP-Ig). Specific IgG levels for group C meningococci were measured by ELISA (Wyeth Laboratories, Rochester, USA) and for a random sample of children at 5 months of age titres were also measured using a functional bactericidal assay (Wyeth-Lederle Laboratories, UK). A minimum antibody level of ] 0.01 IU/ml is considered protective against tetanus and diphtheria with ideal levels ] 0.1 IU/ml. For protection against H. influenzae type b disease, a lower limit for anti-PRP antibodies of ] 0.15 mg/ml is required, while recommended post-vaccination levels are ] 1.0 mg/ml. Although a protective antibody level against group C meningococci has yet to be demonstrated formally, a level above 2 mg/ml is considered likely to be protective [10]. On a randomly selected subgroup of the 5-month sera, the bactericidal activity was also quantified. The assay used measures the average final dilution of serum resulting in ]50% killing of Neisseria meningitidis C strain C11 in the presence of freshly thawed baby rabbit complement compared with similarly treated control organisms lacking patient serum [11].
2.5. Ethical appro6al Prior to the start of the study, ethical approval was received from the Central Oxford Research Ethics Committee. Specific approval was sought from the general practitioners in the pre-defined study areas before eligible infants were approached, and written informed consent from a parent was required before an infant entered the study.
2.6. Sample size, data handling and statistical analysis The primary aim of the study was to determine the response to meningococcal C conjugate vaccine. A sample size of 120 infants in each group was chosen to be able to detect a 1.5-fold difference in the geometric mean titre (GMT) of specific IgG against group C meningococci between active and comparator groups with 80% power at P =0.05, assuming a (natural log) standard deviation of 1.0 (based on previous data). This sample size would also allow approximately 1.6and 1.9-fold differences in the GMTs of antibodies against diphtheria and PRP (Hib) between the groups (testing for interaction) to be detected with similar power All data were recorded in individual case reference forms identified by a study number. Data were then double entered, and range and consistency checked and verified by an independent data management company (SGS Biopharma, Belgium) prior to analysis. Compari-
son of dichotomous outcomes was made using Fisher’s exact test. Absolute antibody levels and titres were log-transformed prior to analysis, the geometric means (presented with 95% confidence intervals) in each study group being compared using the t-test. Within-patient comparisons of local reactions to study and routine vaccines were carried out using McNemar’s test for matched pairs. The principal analysis was performed on an intention-to-treat basis, and all analyses were performed by investigators in Oxford using the software programme STATA 6.0 (Stata Corporation, USA).
3. Results The allocation of infants and their course within the trial is given in Fig. 1. Five of the randomised infants were withdrawn from the study, three at the parents request (two hepatitis B group, one meningococcal group) and two with severe systemic adverse reactions (one hepatitis B group with inconsolable crying, one meningococcal group with fever of 40°C). There were no severe local reactions. There were no other adverse reactions thought to be probably or definitely related to vaccination. Three adverse events were considered possibly related but these did not result in withdrawal of infants from the study. They was mild eczema after third vaccinations (meningococcal group), persistent crying after third vaccinations (hepatitis B group) and irritability with mild fever after third vaccinations (hepatitis B group). One further child received the wrong vaccine at the third visit and no specimen was taken for analysis at 5 months. In addition, no blood was available for analysis at 5 months from five children in the meningococcal group (venesection attempts failed, n= 3; broken specimen tube, n= 1; sample not taken because delay from second to third dose of vaccines was 58 days, n=1). As a result, data from 237 infants (116 meningococcal group and 121 hepatitis B group) were available for an intention to treat analysis of immunogenicity. All vaccination episodes including those up until the time of withdrawal in those leaving the study were included in the assessment of adverse events and tolerability (total=732). Seven children would have been excluded from a strict per-protocol analysis of immunogenicity, four in the meningococcal group and three in the control group. Reasons for per-protocol exclusions included: study vaccine given after maximum permissable time from preparation (one vaccine episode in each of two patients in the meningococcal group); number of days between vaccinations B 28 days or \42 days (five episodes in three hepatitis B group patients and two meningococcal group patients). The exclusion of these
M. English et al. / Vaccine 19 (2001) 1232–1238
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Fig. 1. Trial profile.
latter patients and performance of a strict per-protocol analysis did not significantly alter any of the study findings (data available on request) and thus only the intention-to-treat analysis is presented. In addition, although it could be shown that the magnitude of the 2-month concentration was a statistically significant determinant of the 5-month concentration, only unadjusted comparisons are reported. Including 2-month concentrations as a co-variate in the analyses made no clinical difference to the magnitude of the results and no difference to the significance of statistical comparisons. The basic demographic details and baseline antibody concentrations of those included in the intention to treat analysis are given in Table 1. There were no significant differences between the meningococcal and hepatitis B control groups. The results of antibody assays at 5 months are presented in Table 2. Meningococcal group C antibody titres were 248 (95% CI, 194 317) times higher in the intervention group than in the control group. Antibodies to PRP and Diphtheria were likewise, respectively, 2.5 (95% CI, 1.7, 3.7) and 1.6 (95% CI, 1.3, 2.0) times higher in the intervention compared with the control group. There were no significant differences in the ratios of the geometric mean concentrations for the other antibodies. Serum bactericidal assays were performed on specimens collected at 5 months on 117 children, 58 of whom received meningococcal vaccine. Geometric mean titres were 2.9 (95% CI, 1.8, 4.9) in the control group and 1428.7 in the meningococcal group (95% CI, 1125.1, 1814.3). The pattern of responses determined by ELISA and SBA titre in the intervention and control groups, and the
relationship between the SBA titres and the ELISA concentrations are depicted in Fig. 2. All 58 children receiving the meningococcal vaccine with samples analysed achieved both an ELISA-measured specific Table 1 Demographic and baseline serological data Meningococcal C group (n =116) [95% CI] Percentage male 56% [47%, 65%] Age at first 61.1 [60.4, 61.9] blood/vaccination (days) Age at second blood 153.7 [152.1, 155.3] (days) Geometric mean 0.17 [0.14, 0.21] PRP titre (mg/ml) Geometric mean 0.13 [0.10, 0.17] meningococcal C titre (mg/ml) Geometric mean 0.50 [0.41, 0.61] tetanus titre (IU/ml) Geometric mean 0.01 [0.01, 0.01] Diphtheria titre (IU/ml) Geometric mean 2.93 [2.38, 3.60] pertussis toxoid (U/ml) Geometric mean 9.15 [7.61, 11.0] pertussis FHA (U/ml) Geometric mean 0.79 [0.66, 0.95] pertussis fimbriae (U/ml)
Hepatitis B group (n =121) [95% CI]
55% [45%, 63%] 60.2 [59.4, 61.0]
152.6 [151.2, 154.1] 0.15 [0.12, 0.19] 0.17 [0.12, 0.22]
0.55 [0.44, 0.68]
0.01 [0.01, 0.01]
3.28 [2.66, 4.04]
8.34 [6.93, 10.0]
0.91 [0.75, 1.10]
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Table 2 Serological response at 5 months to vaccination schedule (ITT analysis)a Meningococcal C group (n =116) [95% CI] Response to study vaccines Response to Hib vaccine Response to diphtheria toxoid Response to tetanus toxoid Response to pertussis vaccine.
Geometric mean meningococcal C 23.93 [21.47, 24.68] concentration (mg/ml) Proportion ]2.0 (mg/ml) 100% [96%, 100%] Geometric mean PRP concentration (mg/ml) 9.83 [7.72, 12.50] Proportion ]1.0 (mg/ml) 94% [88%, 97%] Proportion ]0.15 (mg/ml) 100% [96%, 100%] Geometric mean (IU/ml) Diphtheria 1.77 [1.54, 2.04] concentration Proportion ]0.1 (IU/ml) 100% [96%, 100%] Geometric mean tetanus concentration (IU/ml) 5.81 [5.06, 6.68]
Hepatitis B group (n = 121) [95% CI]
P value for difference
0.10 [0.08, 0.12]
B0.001
4% [2%, 10%] 3.90b [2.91, 5.22] 78% [69%, 84%] 99% [95%, 100%] 1.07b [0.93, 1.25]
B0.001 B0.001 B0.001 1.0 B0.001
100% [96%, 100%] 6.39 [5.52, 7.39]
– 0.4
Geometric mean pertussis toxoid concentration (U/ml)
4.23 [3.48, 5.14]
4.47 [3.66, 5.47]
0.7
Geometric mean pertussis FHA concentration (U/ml) Geometric mean pertussis fimbriae concentration (U/ml)
15.38 [13.46, 17.57]
15.43 [13.24, 17.98]
1.0
25.01 [21.24, 29.25]
26.59 [22.22, 31.82]
0.6
a There were no differences in the proportions of children achieving tetanus titres ]0.01 or 0.1 between groups and no differences in proportions achieving a twofold or greater rise in pertussis responses between groups. b n= 120.
IgG \ 2 mg/ml and an SBA titre \1 in 8 at 5 months, both thought to be clinically significant responses. Among the 59 control children tested, eight demonstrated a SBA titre\ 1 in 8 without achieving a specific IgG response \ 2 mg/ml, and three had a specific IgG response \2 mg/ml but a low or absent response in the SBA assay. Data from more than 93% of vaccination episodes were available for examining the prevalence of mild systemic adverse reactions that were commonly reported (illustrated with data from the 4-month vaccinations in Table 3). Temperatures were available for analysis in 89% of cases and, in these, fever was uncommon (B 3% episodes overall were associated with a temperature \37.9°C). No statistically significant differences in reporting were observed between treated and control groups at 2, 3 or 4 months. Comparison of local reactions to the hepatitis B vaccine and meningococcal group C vaccine also failed to demonstrate any difference at any stage (illustrative data at 4 months is given in Table 3). However, local reactions to the study vaccines were also compared with the simultaneously administered routine DTP/Hib vaccines given in a different leg. Routine vaccines were associated with redness and swelling (of any degree) more often than either study vaccine at each dose (P 5 0.01 for each comparison), although such an obvious difference was not apparent for tenderness (illustrative data at 4 months is given in Table 3).
4. Discussion Three doses of a vaccine comprising the meningococcal group C oligosaccharide conjugated to CRM197 (a variant diphtheria toxoid) with an alum adjuvant produced a marked, specific IgG response when administered to 116 children at 2, 3 and 4 months of age. The geometric mean meningococcal group C antibody titre (23.9 mg/ml) was comparable with results in previous
Fig. 2. Scatter plot of log2 values of meningococcal group C serum bactericidal titre (y axis) and log10 antibody concentration (mg/ml) measured by ELISA (x axis) from individuals aged 5 months. Grey circles, Meningococcal group C conjugate vaccine recipients (n= 59); black squares, ELISA concentrations \2 mg/ml are found to the right of the dashed, vertical line, and SBA titres \1 in 8 are found above the solid horizontal line.
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Table 3 Proportion of children vaccinated at 4 months (third vaccination) with associated systemic and local adverse reactions during the 3-day observation period
Crying more than expected Fever ]38°C Irritability Sleeping through a feed Any redness at study vaccine site Any swelling at study vaccine site Any tenderness at study vaccine site Any redness at routine vaccine site Any swelling at routine vaccine site Any tenderness at routine vaccine site
Meningococcal C Group (maximum n=122)
Hepatitis B group (maximum n = 121)
P value for difference
15/115 5/101 81/121 24/114 46/113 7/112 15/113 66/115 28/113 20/111
9/109 (8%) 1/98 (1%) 75/112 (67%) 14/109 (13%) 45/113 (40%) 9/111 (8%) 16/110 (15%) 63/112 (56%)b 20/110 (18%)b 21/110 (19%)b
0.3 0.2 1.0 0.11 1.0 0.6 0.8
(13%) (5%) (67%) (21%) (41%) (6%) (13%) (57%)a (25%)a (18%)a
a Number of matched pairs for analysis is 112, 110 and 111 for redness, swelling and tenderness, respectively; PB0.01 for comparison of proportions for those experiencing any redness or swelling at meningococcal vaccine site and routine vaccine site. b Number of matched pairs for analysis is 111, 109 and 109 for redness, swelling and tenderness, respectively; PB0.01 for comparison of proportions for those experiencing any redness or swelling at Hepatitis B vaccine site and routine vaccine site.
studies using similar vaccines (GMT=38.59 mg/ml [12] and 13.1 mg/ml [6]) although non-IgG-specific ELISAs were used in the these studies. In one of these previously reported studies [12], all 56 children receiving a meningococcal group C conjugate vaccine at the UK schedule achieved an antibody concentration \ 2 mg/ml at 5 months, as occurred in our study. In both cases, this was associated with serum bactericidal activity ] 1 in 8 (a titre thought likely to protect individuals from disease [10]) in all children. Another recent UK study using a different meningococcal group C conjugate vaccine reported similar results in 62 children in whom serum bactericidal titres were measured [7]. These studies therefore provide important evidence that a functional immune response results from this class of vaccine. Interestingly, however, despite the obvious concordance of results from the ELISA assays and serum bactericidal assays in children receiving the meningococcal conjugate vaccine among control children, high concentrations of specific IgG antibody and high titre serum bactericidal activity, when present, were often discrepant (Fig. 2). One explanation might be the presence of naturally acquired non-IgG immunoglobulin classes in the functional assay that would not be detected using the IgG-specific ELISA technique. As important to a national immunisation programme as the immunogenicity data presented in this paper are recent data indicating that meningococcal group C conjugate vaccines are also likely to induce effective immunologic memory, and thus long-lasting immunity [6,7] after administration at 2, 3 and 4 months. In practice, acceptance of this vaccine may also be aided as it appears to be well tolerated with few systemic reactions or significant local reactions occurring. How-
ever, although meningococcal group C disease is a major public health issue, it is still a relatively rare disease. Proving the effectiveness and safety of this vaccine will therefore either depend on the conduct of extremely large intervention trials ( 500 000 infants [12]) or reliable disease surveillance as part of the intervention program. Paradoxically, demonstrating effectiveness may become easier if the currently high incidence of meningococcal disease [4] is sustained and reliable information on the serogroup of invasive isolates continues to be available. While the overwhelming majority of cases of meningococcal disease in the United Kingdom are attributed to group B or group C organisms, this is not always the case world-wide. Group A organisms are responsible for major epidemics, particularly in the sub-Sahelian states of Africa [13], while group Y and group W135 organisms may cause a significant number of cases in some countries [14,15]. Clearly, a group C specific vaccine will not protect against these other pathogens. Three factors may therefore limit the apparent degree of protection afforded by this vaccine: travel to areas where non-group C organisms are common [16]; a change in the epidemiology of invasive disease (particularly the emergence of group A, Y or W135 disease) [15]; or the possibility that the vaccine will induce an adaptive switch to other capsular groups or non-encapsulated forms [15,17,18]. Multivalent meningococcal vaccines may provide a partial answer to some of these problems. However, multivalent pneumococcal conjugate vaccines (seven to nine serotypes) are also being assessed in Phase III trials [19], and these pneumococcal vaccines may be available to national immunisation programmes shortly. The possible effects on current routine vaccina-
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tions therefore require consideration. In this study, a positive interaction was demonstrated between vaccines with some structural similarities (diphtheria toxoid, and the Hib and meningococcal conjugate vaccines that use a variant diphtheria toxoid as a carrier). One possible mechanism for this is the generation of a large cross-reactive T helper cell population. While this may be beneficial, some work has already suggested that, as the dose of a specific carrier protein administered increases, there may be a deleterious effect on response to vaccines. Thus, using a four-valent pneumococcal – tetanus toxoid conjugate in infants also receiving a Hib– tetanus toxoid conjugate and tetanus toxoid alone, Dagan et al. demonstrated a fall in response to the Hib and tetanus vaccines as the total dose of carrier (tetanus toxoid) increased [20]. As the effect on seroconversion rates was marginal, the significance of this finding is hard to gauge, but clearly such a possibility needs to be considered as an increasing number of vaccines become available. Furthermore, if public confidence is to be maintained, clear evidence will be required of the potential benefits and safety of an ever-expanding vaccination strategy.
[4] [5]
[6]
[7]
[8]
[9]
[10] [11]
Acknowledgements The contributions made by the authors were as follows: Mike English, involved in design, data collection, analysis and preparation of the manuscript; Jenny MacLennan, contributed to design, data collection and preparation of the manuscript; Jane Bowen-Morris, contributed to design, data collection and preparation of the manuscript; Jon Deeks, contributed to design, analysis and preparation of the manuscript; Maggie Boardman, Jim Buttery, Karen Brown and Sandra Smith, contributed to data collection and preparation of the manuscript; S. Quataert, responsible for development of the specific laboratory assays and the performance of these assays; and Jane Clarke, Steven Lockhart and Prof. E.R. Moxon, responsible for initiating the study, contributed to design and preparation of the manuscript.
[12]
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